Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive sphingolipid metabolite that is now emerging as an important regulator of many physiological and pathological processes in health and diseases. S1P is produced intracellularly by two closely related sphingosine kinases, SphK1 and SphK2. Although much has been learned about SphK1 and its functions, those of SphK2 remained enigmatic. We recently found that SphK2, which is present in the nucleus, produces S1P that specifically binds to histone deacetylases HDAC1/2 and inhibits their enzymatic activities, linking sphingolipid metabolism and S1P in the nucleus to epigenetic regulation of gene expression. Hence, we suggested that S1P is an endogenous small molecule regulator of these enzymes, which opens a fascinating scenario for sphingolipid signaling in the nucleus and for HDAC regulation. HDAC1/2 belongs to a large family of zinc-dependent HDACs, and HDAC inhibitors have long been used in psychiatry and various neurological disorders. However, despite the widespread interest in HDACs, the environmental cues and signal transduction pathways that regulate their activity, as well as endogenous regulators remain largely unknown. In Aim 1 of this proposal, we will examine the role of S1P produced by SphK2 in the nucleus as an endogenous regulator of HDACs, histone acetylations, and gene expression, independently of S1P receptor signaling. The discovery that the immunomodulator FTY720, which opened new approaches for the treatment of multiple sclerosis, is a pro-drug that is phosphorylated in vivo by SphK2 to a mimetic of S1P raised the intriguing possibility that it also mimics the nuclear actions of S1P. Therefore, in Aim 2 we will analyze the potential of FTY720 and other S1P receptor modulators as regulators of HDACs and histone acetylations. As HDACs have emerged as key targets to reverse aberrant epigenetic changes associated with memory deficits, we will use genetic, molecular, and pharmacological approaches in Aim 3 to decipher the in vivo role of the SphK2/S1P axis and FTY720 in histone acetylation, gene regulation, and contextual memory in mice. Our proposal will uncover new actions of FTY720, and potentially other S1P mimetics, as specific HDAC inhibitors and constitute an initial test of the capacity of manipulating the epigenome to potentially reverse memory dysfunction associated with aging, multiple sclerosis, and other neurological diseases. Understanding how the SphK2/S1P axis regulates functions of HDACs should provide fundamental insights into the molecular and cellular basis of chromatin modifications and their involvement in memory and may pave the way for effective therapies aimed at cognitive disorders.